The ultimate goal of treatment for Alzheimer's disease (AD) is to prevent degeneration of brain neurons and synapses. We screened a variety of generic drugs for neuroprotective effect using cell culture and animals models of AD immune pathology. One widely used generic drug with anti-inflammatory properties was found to be highly neuroprotective in cell culture and animal models. Although the same drug showed some clinical benefit, its level of effect was not sufficient to offer a useful therapy. For this reason, we sought to design more potent forms of this generic drug lead. A target discovery program has now identified 4 classes of analogs derived from the parent compound that show >20-fold increase in neuroprotective effect in vitro and improved disease-modifying action against AD pathology in vivo. Importantly, these novel analogs have been designed to eliminate the major dose-limiting toxic side effect of the parent drug. This Phase 2 SBIR proposal seeks to further optimize the analogs for brain penetrating capacity while retaining potency and margins of safety in vivo. Successful completion of Phase 2 will allow selection of a drug, and its backup, for final pre-clinical development. PUBLIC HEALTH RELEVANCE: At the present time there are no effective treatments for Alzheimer's disease. This dementia is a neurodegenerative disorder characterized by loss of memory, declining motor function, and behavioral changes. Death of neurons caused by toxins generated Alzheimer's disease in the brain is thought to be the cause of the dementia. More research is needed to develop effective treatments that will both reduce brain injury and improve intellectual functions in the Alzheimer's disease patient. The proposal submitted here encompasses pre-clinical research on compounds that may help neuron survival and brain function. Exploration of these agents should accelerate the national effort to identify therapies for the prevention of dementia and /or the improvement cognitive function in the Alzheimer's Disease population. .